• Gastrointestinal Cancers
• Adjuvant/Neoadjuvant Therapy

The results of a National Surgical Adjuvant Breast and Bowel Project (NSABP) (NCT00096278) trial indicate that bevacizumab is safe when it is given as postoperative adjuvant therapy (in conjunction with conventional chemotherapy) to patients with stage II or stage III colorectal cancer. The efficacy data from the study are not yet available, but the safety data were reported first because of the potential effect on ongoing or planned investigations that involve bevacizumab and other antiangiogenic agents.

Carmen J. Allegra, MD, University of Florida, Gainesville, FL, reported the initial safety data from NSABP C-08. This randomized phase 3 trial was designed to compare modified FOLFOX6 (5-FU/leucovorin plus oxaliplatin) with and without bevacizumab. The primary endpoint was disease-free survival. One of the most important findings of the safety analysis, said Dr. Allegra, is that bevacizumab is safe in the postoperative period in the patient population that is eligible for C-08. It is not clear how far the data can or should be extrapolated beyond the eligible population. “The fear has been that, as an antiangiogenic agent, bevacizumab could have serious toxicity for postoperative patients. This was not borne out in the study,” he said.

The trial enrolled 2710 patients who were randomly assigned to either FOLFOX6 every 2 weeks for 12 doses or the same chemotherapy regimen with bevacizumab given every 2 weeks for 26 doses. Patients were assigned to a treatment group after Day 29 and before Day 50 postoperatively. The data that were presented by Dr. Allegra represented findings for 1321 patients who were treated with FOLFOX6 alone and 1326 who were treated with FOLFOX6 plus bevacizumab. The mean duration of follow-up was 28.5 months.

The addition of bevacizumab did not adversely affect the dose intensity of FOLFOX6. Dr. Allegra noted that the median dose intensity was 40.6 mg/m2/wk for FOLFOX6 alone and 41.6 mg/m2/wk for FOLFOX6 plus bevacizumab (p=0.13). A significantly greater percentage of patients who were treated with FOLFOX6 plus bevacizumab received at least 10 of the 12 doses of 5-FU (85% vs 80%; p<0.01) and oxaliplatin (78% vs 73%; p<0.01).

Dr. Allegra reported that bevacizumab was not associated with a significant increase in several toxicities that have been found in other studies of advanced disease, such as cardiac, central nervous system, or peripheral arterial ischemia; gastrointestinal perforation; or hemorrhage. Bevacizumab was associated with significantly fewer occurrences of thrombocytopenia (1.4% vs 3.4% for FOLFOX6 alone; p<0.001) and allergic reaction (3.1% vs 4.7%; p=0.03).

There was no difference between the early mortality in each group. Within 6 months of random assignment, the mortality rate was 0.96% for FOLFOX6 alone and 0.90% for FOLFOX6 plus bevacizumab (p=1.0). At 18 months, the corresponding mortality rates were 1.33% and 1.35% (p=1.0).

Most of the adverse events were grade 3, and these events occurred in significantly more patients in the FOLFOX6 plus bevacizumab group (p=0.0006). All of the adverse events were manageable, added Dr. Allegra. To isolate the effects of bevacizumab, the researchers evaluated adverse events that occurred in the 12 months that followed the completion of chemotherapy (Table 1). Focusing on wound complications, Dr. Allegra noted that all such complications were grade 3 and that they resulted in surgical intervention in all but one case and in discontinuation of bevacizumab in half of the cases. Most of the wound complications (63%) were symptomatic abdominal incisional hernias, and 37% was dehiscence, infection, or inflammation at the site of the infusion port. The median time to occurrence of the wound complications was 5 months for hernias and 2 months for the infusion port-related complications.

Dr. Allegra concluded that despite the safety of bevacizumab, it cannot be recommended in the adjuvant setting until data provide evidence of its efficacy.

In his discussion of the study, Richard M. Goldberg, MD, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, said that he agreed that bevacizumab was safe in the setting of adjuvant therapy for stage II or III colorectal cancer. He pointed out that the rates of early mortality were similar to those in other adjuvant studies.

Dr. Goldberg commented that the increased frequency of pain among patients who were treated with bevacizumab was a surprise. However, he added, “There have been some studies of other angiogenesis inhibitors in which patients have reported modest pain.” In closing, he reiterated the need for more data to determine the long-term toxicity or benefit of bevacizumab.

• © 2008 MD Conference Express